The GDNF family ligands (GFLs - GDNF, neurturin, artemin and persephin) are a family of neurotrophic factors of critical importance to neurodevelopment, and are potential therapeutic agents for many neurodegenerative diseases from Parkinson's disease to peripheral neuropathy. GFLs signal through a multimolecular complex comprised of RET (a receptor tyrosine kinase) and a specific ligand-binding coreceptor, GFRa1-4. The expression pattern of RET and the different GFRas is critical to mediate responsiveness to a particular GFL and proper neurodevelopment, but the genetic network underlying regulation of these receptors in specific neuronal subtypes remains unknown. GFLs can alter addictive behaviors through their influence on the ventral tegmental area, broadening their relevance to another critical population of midbrain dopaminergic neurons, and opening a new avenue in the treatment of substance addiction. GFLs and their receptors are expressed in the retina, and exogenous GDNF can slow retinal degeneration. Although the critical role GFLs play in peripheral nervous system development, and their promise as therapeutic agents for Parkinson's disease are firmly established, much work remains to be done to characterize the role of GFLs particularly in postnatal central nervous system development and maintenance, and to optimize and broaden their therapeutic potential into different avenues. With these goals in mind, we propose the following specific aims: (1) to identify the genetic network that regulates the expression of GFL receptors in different cell types using bioinformatics analysis of RET and the GFRa loci, together with targeted in vitro and in vivo confirmation, (2) to characterize the importance of RET signaling in midbrain dopaminergic neurons in adult animals, in regards to susceptibility to Parkinsonism-inducing toxins and modulation of addictive behaviors, using conditional removal of RET from dopaminergic neurons in transgenic mice, (3) to characterize the role of Neurturin-RET signaling in retinal development/maintenance using transgenic mice, and to investigate the utility of GFLs in a mouse model of retinal degeneration. Relevance: Neurodegenerative diseases are a tremendous burden to the public, with few effective treatments. Neurotrophic factors such as the GFLs have potential in relieving this burden, and the research in the proposal is aimed at furthering that potential.